Substituted oxazolidinones and use thereof

Abstract

The invention relates to novel substituted oxazolidinones, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular of thromboembolic disorders.

1 . Compound of the formula 
     
       
         
         
             
             
         
       
       in which 
       R 1  represents a group of the formula 
     
     
       
         
         
             
             
         
       
       where 
       # is the point of attachment to the phenyl ring, 
       R 4  represents hydrogen or C 1 -C 3 -alkyl, 
       where alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, C 1 -C 3 -alkoxy and C 3 -C 6 -cycloalkyloxy, 
       R 5  represents hydrogen, hydroxyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or C 3 -C 6 -cycloalkyloxy, 
       where alkyl and alkoxy may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, C 1 -C 3 -alkoxy and C 3 -C 6 -cycloalkyloxy, 
       R 6  represents hydrogen, hydroxyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or C 3 -C 6 -cycloalkyloxy, 
       where alkyl and alkoxy may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, C 1 -C 3 -alkoxy and C 3 -C 6 -cycloalkyloxy, 
       R 7  represents hydrogen, C 1 -C 3 -alkyl or C 3 -C 6 -cycloalkyl, 
       where C 2 -C 3 -alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, C 1 -C 3 -alkoxy and C 3 -C 6 -cycloalkyloxy, 
       R 8  represents hydrogen, C 1 -C 3 -alkyl or C 3 -C 6 -cycloalkyl, 
       where C 2 -C 3 -alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, C 1 -C 3 -alkoxy and C 3 -C 6 -cycloalkyloxy, 
       R 9  represents hydrogen, C 1 -C 3 -alkyl or C 3 -C 6 -cycloalkyl, 
       where C 2 -C 3 -alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, C 1 -C 3 -alkoxy and C 3 -C 6 -cycloalkyloxy, 
       R 10  represents hydrogen, C 1 -C 3 -alkyl or C 3 -C 6 -cycloalkyl, 
       where C 2 -C 3 -alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, C 1 -C 3 -alkoxy and C 3 -C 6 -cycloalkyloxy, 
       R 11  represents hydrogen, hydroxyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or C 3 -C 6 -cycloalkyloxy, 
       where alkyl and alkoxy may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, C 1 -C 3 -alkoxy and C 3 -C 6 -cycloalkyloxy, 
       R 12  represents hydrogen, C 1 -C 3 -alkyl or C 3 -C 6 -cycloalkyl, 
       where C 2 -C 3 -alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, C 1 -C 3 -alkoxy and C 3 -C 6 -cycloalkyloxy, 
       R 2  represents fluorine, chlorine, cyano, trifluoromethyl or trifluoromethoxy, 
       R 3  represents hydrogen, chlorine, methyl, ethyl, n-propyl, methoxy, ethoxy or methoxymethyl, 
       or one of its salts, its solvates or the solvates of its salts. 
     
   
   
       2 . Compound according to  claim 1 , characterized in that
 R 1  represents a group of the formula   
     
       
         
         
             
             
         
       
       where 
       # is the point of attachment to the phenyl ring, 
       R 4  represents hydrogen, 
       R 5  represents hydrogen, hydroxyl, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy, 
       where alkyl and alkoxy may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl and C 1 -C 3 -alkoxy, 
       R 6  represents hydrogen, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy, 
       where alkyl and alkoxy may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl and C 1 -C 3 -alkoxy, 
       R 8  represents hydrogen, C 1 -C 3 -alkyl or C 3 -C 6 -cycloalkyl, 
       where C 2 -C 3 -alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl and C 1 -C 3 -alkoxy, 
       R 9  represents hydrogen, C 1 -C 3 -alkyl or C 3 -C 6 -cycloalkyl, 
       where C 2 -C 3 -alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl and C 1 -C 3 -alkoxy, 
       R 10  represents hydrogen, C 1 -C 3 -alkyl or C 3 -C 6 -cycloalkyl, 
       where C 2 -C 3 -alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl and C 1 -C 3 -alkoxy, 
       R 2  represents fluorine or chlorine, 
       R 3  represents hydrogen, methyl or methoxymethyl, 
       or one of its salts, its solvates or the solvates of its salts. 
     
   
   
       3 . Compound according to  claim 1  or  2 , characterized in that
 R 1  represents a group of the formula   
     
       
         
         
             
             
         
       
       where 
       # is the point of attachment to the phenyl ring, 
       R 4  represents hydrogen, 
       R 5  represents hydrogen, hydroxyl or hydroxymethyl, 
       R 6  represents hydrogen, methyl, hydroxymethyl, 2-hydroxyeth-1-yl or 2-hydroxyeth-1-oxy, 
       R 8  represents hydrogen or methyl, 
       R 9  represents hydrogen or methyl, 
       R 10  represents methyl, ethyl or 2-hydroxyeth-1-yl, 
       R 2  represents fluorine or chlorine, 
       R 3  represents hydrogen or methyl, 
       or one of its salts, its solvates or the solvates of its salts. 
     
   
   
       4 . Compound according to any of  claims 1  to  3 , characterized in that
 R 1  represents a group of the formula   
     
       
         
         
             
             
         
       
       where 
       # is the point of attachment to the phenyl ring, 
       R 4  is hydrogen, 
       R 5  is hydrogen, hydroxyl or hydroxymethyl, 
       R 6  is hydroxymethyl or 2-hydroxyeth-1-oxy, 
       R 2  is fluorine or chlorine, 
       R 3  is hydrogen or methyl, 
       or one of its salts, its solvates or the solvates of its salts. 
     
   
   
       5 . Process for preparing a compound of the formula (I) or one of its salts, its solvates or the solvates of its salts according to  claim 1 , characterized in that
 [A] a compound of the formula   
     
       
         
         
             
             
         
       
       is, in the first step, reacted with a compound of the formula 
     
     
       
         
         
             
             
         
       
       in which R 1 , R 2  and R 3  have the meaning given in  claim 1 , 
       to give a compound of the formula 
     
     
       
         
         
             
             
         
       
       in which R 1 , R 2  and R 3  have the meaning given in  claim 1 , 
       and, in the second step, this compound is cyclised in the presence of phosgene or phosgene equivalents to give a compound of the formula (I), 
       or 
       [B] a compound of the formula 
     
     
       
         
         
             
             
         
       
       in which R 1 , R 2  and R 3  have the meaning given in  claim 1   
       is reacted with a compound of the formula 
     
     
       
         
         
             
             
         
       
       in which 
       X represents halogen, preferably bromine or chlorine, or hydroxyl. 
     
   
   
       6 . Compound according to any of  claims 1  to  4  for the treatment and/or prophylaxis of diseases. 
   
   
       7 . Use of a compound according to any of  claims 1  to  4  for preparing a medicament for the treatment and/or prophylaxis of diseases. 
   
   
       8 . Use of a compound according to any of  claims 1  to  4  for preparing a medicament for the treatment and/or prophylaxis of thromboembolic disorders. 
   
   
       9 . Use of a compound according to any of  claims 1  to  4  for preventing blood coagulation in vitro. 
   
   
       10 . Medicament, comprising a compound according to any of  claims 1  to  4  in combination with an inert nontoxic pharmaceutically acceptable auxiliary. 
   
   
       11 . Medicament comprising a compound according to any of  claims 1  to  4  in combination with a further active compound. 
   
   
       12 . Medicament according to  claim 10  or  11  for the treatment and/or prophylaxis of thromboembolic disorders. 
   
   
       13 . Method for the treatment and/or prophylaxis of thromboembolic disorders in humans and animals using an anticoagulatory effective amount of at least one compound according to any of  claims 1  to  4 , a medicament according to any of  claims 10  to  12  or a medicament obtained according to  claim 7  or  8 . 
   
   
       14 . Method for preventing blood coagulation in vitro, characterized in that an anticoagulatory effective amount of a compound according to any of  claims 1  to  4  is added. 
   
   
       15 . Use of a compound according to any of  claims 1  to  4  for preparing a medicament for the treatment and/or prophylaxis of pulmonary hypertension. 
   
   
       16 . Use of a compound according to any of  claims 1  to  4  for preparing a medicament for the treatment and/or prophylaxis of sepsis, systemic inflammatory syndrome (SIRS), septic organ dysfunction, septic organ failure and multiorgan failure, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), septic shock, DIC (“disseminated intravascular coagulation”) and/or septic organ failure. 
   
   
       17 . Compound, as defined in one of  claims 1  to  4 , for use in a method for the treatment and/or prophylaxis of thromboembolic disorders.